Analysis of Nifedipine Absorption from Soft Gelatin Capsules Using PBPK Modeling and Biorelevant Dissolution Testing
Analysis of Nifedipine Absorption from Soft Gelatin Capsules Using PBPK Modeling and Biorelevant Dissolution Testing
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DOI：
10.1002/jps.22026
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发表时间：
2010-06-01
影响因子：
3.8
通讯作者：
Willmann, Stefan
中科院分区：
文献类型：
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作者：
Thelen, Kirstin;Jantratid, Ekarat;Willmann, Stefan
据报道，空腹志愿者服用20 mg硝苯地平速释软胶囊后吸收延迟。基于生理学的药代动力学（PBPK）建模和体外溶出数据被用来探讨我们的假设，即在高剂量的硝苯地平，它沉淀在胃中。使用商业PBPK软件模拟不同剂量硝苯地平后的血药浓度-时间曲线，并与体内数据进行比较。用Adala（R）10 mg胶囊在不同体积的禁食状态模拟胃液（FaSSGF）中进行体外溶出试验。假设20 mg剂量的溶出时间延长，可以很好地模拟不同硝苯地平剂量之间的血药浓度-时间曲线差异。硝苯地平从一粒Adalat 10胶囊在250或500 mL FaSSGF中的释放在15 min内完成，而当从两粒胶囊（对应于20 mg硝苯地平）在250 mL FaSSGF中的释放进行研究时，在15 min后观察到最大约75%的药物溶解，随后溶解%下降至约40%的最终值。根据计算机模拟和体外结果，可以得出结论，20 mg剂量后观察到的硝苯地平吸收延长可能是由硝苯地平在人胃中沉淀引起的。(C)2009 Wiley-Liss，Inc.和American Pharmacologist Association J Pharm Sci 99：2899-2904，2010
Delayed absorption of nifedipine when administered as a 20 mg immediate release soft gelatin capsule to fasted volunteers has been reported. Physiologically based pharmacokinetic (PBPK) modeling and in vitro dissolution data were used to explore our hypothesis that at high doses of nifedipine it precipitates in the stomach. Plasma concentration time profiles following different doses of nifedipine were simulated using commercial PBPK software and compared to in vivo data. In vitro dissolution tests were performed with Adala (R) 10 mg capsules in different volumes of fasted state simulated gastric fluid (FaSSGF). The discrepancy in plasma concentration time profiles between the different nifedipine doses could be well simulated, assuming protracted dissolution for the 20 mg dose. Nifedipine release from one Adalat 10 capsule in 250 or 500 mL FaSSGF was completed within 15 min whereas when release from two capsules, corresponding to 20 mg nifedipine, was studied in 250 mL FaSSGF, a maximum of about 75% drug dissolved was observed after 15 min followed by a decline in the % dissolved to a final value of approximately 40%. Based on the in silico and in vitro results it can be concluded that the observed prolongation in nifedipine absorption following the 20 mg dose was likely caused by nifedipine precipitation in human stomach. (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:2899-2904, 2010